The transcriptional repressor protein BCL6 has been implicated in the pathogenesis of non-Hodgkin?s lymphoma, but little is known about the normal function of BCL6. We have previously shown that the targeted disruption of the BCL6 gene leads to Th2-mediated inflammation, suggesting that BCL6 plays an important role in the regulation of T helper type 2 (Th2) subset differentiation. The cytokine IL-4 and the transcription factor STAT6 are critical mediators of Th2 differentiation. We have found that BCL6 regulates a novel pathway of Th2 differentiation that is independent of IL-4 and STAT6. Our hypothesis is that the cytokine IL-6 has a unique ability to induce Th2 differentiation via this IL-4/STAT6-independent pathway. In this proposal, we plan to use mouse genetic, cellular and molecular techniques to study the mechanisms by which BCL6 regulates this novel pathway of Th2 differentiation. These studies will provide important insights into normal Th2 differentiation, which may lead to new understanding of allergic diseases such as asthma. These studies will also provide insight into the function of BCL6, which may help the treatment of B cell lymphoma.